Aβ Immunotherapy: Intracerebral Sequestration of Aβ by an Anti-Aβ Monoclonal Antibody 266 with High Affinity to Soluble Aβ
Open accessAbstract
Amyloid beta (Abeta) immunotherapy is emerging as a promising disease-modifying therapy for Alzheimer's disease, although the precise mechanisms whereby anti-Abeta antibodies act against amyloid deposition and cognitive deficits remain elusive. To test the "peripheral sink" theory, which postulates that the effects of anti-Abeta antibodies in the systemic circulation are to promote the Abeta efflux from brain to blood, we studied the clearance of (125)I-Abeta(1-40) microinjected into mouse brains after intraperitoneal administration of an anti-Abeta monoclonal antibody 266. (125)I-Abeta(1-40) was rapidly eliminated from brains with a half-life of approximately 30 min in control mice, whereas 266 significantly retarded the elimination of Abeta, presumably due to formation of Abeta-antibody complex in brains. Administration of 266 to APP transgenic mice increased the levels of monomer Abeta species in an antibody-bound form, without affecting that of total Abeta. We propose a novel mechanism of Abeta immunotherapy by the class of anti-Abeta antibodies that preferentially bind soluble Abeta, i.e., intracerebral, rather than peripheral, sequestration of soluble, monomer form of Abeta, thereby preventing the accumulation of multimeric toxic Abeta species in brains.
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For certain Aβ antibodies such as m266, increases of peripheral Aβ have been observed because antibody prevented Aβ from being degraded via binding to it and potentially increasing net Aβ efflux out of the brain.
“For certain A antibodies, such as m266, increases of peripheral A has been observed because antibody prevented A from being degraded via binding to it and potentially increasing net A efflux out of the brain (DeMattos et al., 2002;Yamada et al., 2009).”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Yamada et al., 2009
The Introduction reports that m266 increased plasma Aβ and describes reduced clearance of antibody-bound Aβ as an explanation, though it does not establish that binding prevented degradation specifically. The proposed increase in brain-to-blood efflux is not supported by this study: the Discussion reports that m266 instead retarded efflux. (LLM, conf=0.88)
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- Authors
- Yamada, K., Yabuki, C., Seubert, P., Schenk, D., Hori, Y., Ohtsuki, S., Terasaki, T., Hashimoto, T., & Iwatsubo, T.
- Affiliations
- The University of Tokyo (JP)
- Elan Pharmaceuticals, Inc. (Ireland) (IE)
- Tohoku University (JP)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-09-09
- Volume
- 29
- Issue
- 36
- Pages
- 11393-11398
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6665926
- OpenAlex
- W2102347098
- Cited by
- 117
- References
- 10
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 3 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 6 · 2016: 6 · 2015: 7 · 2014: 17 · 2013: 13 · 2012: 11
- FWCI
- 6.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta immunotherapy, Alzheimer's disease, amyloid-beta clearance, APP transgenic mice, amyloid deposition, disease-modifying therapy
- MeSH terms
- Alzheimer Disease, Animals, Antibodies, Monoclonal, Antibody Affinity, Brain, Humans, Injections, Intraventricular, Male, Mice, Inbred C57BL, Mice, Transgenic, Microinjections, Solubility, Amyloid beta-Peptides, Immunotherapy, Active, Mice
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